Proteomic Screening of Human Targets of Viral MicroRNAs Reveals Functions Associated with Immune Evasion and Angiogenesis

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2013 Sep 17

PMID 24039573

Citations 36

Authors

Amelia M Gallaher

Sudipto Das

Zhen Xiao

Thorkell Andresson

Philippe Kieffer-Kwon

Christine Happel

Joseph Ziegelbauer

Affiliations

Soon will be listed here.

Abstract

Kaposi's sarcoma (KS) is caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV). The virus expresses unique microRNAs (miRNAs), but the targets and functions of these miRNAs are not completely understood. In order to identify human targets of viral miRNAs, we measured protein expression changes caused by multiple KSHV miRNAs using pulsed stable labeling with amino acids in cell culture (pSILAC) in primary endothelial cells. This led to the identification of multiple human genes that are repressed at the protein level, but not at the miRNA level. Further analysis also identified that KSHV miRNAs can modulate activity or expression of upstream regulatory factors, resulting in suppressed activation of a protein involved in leukocyte recruitment (ICAM1) following lysophosphatidic acid treatment, as well as up-regulation of a pro-angiogenic protein (HIF1α), and up-regulation of a protein involved in stimulating angiogenesis (HMOX1). This study aids in our understanding of miRNA mechanisms of repression and miRNA contributions to viral pathogenesis.

Citing Articles

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References

Nishiyama A, Xin L, Sharov A, Thomas M, Mowrer G, Meyers E . Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell. 2009; 5(4):420-33. PMC: 2770715. DOI: 10.1016/j.stem.2009.07.012. View

Guo H, Ingolia N, Weissman J, Bartel D . Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010; 466(7308):835-40. PMC: 2990499. DOI: 10.1038/nature09267. View

Manes T, Hoer S, Muller W, Lehner P, Pober J . Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins block distinct steps in transendothelial migration of effector memory CD4+ T cells by targeting different endothelial proteins. J Immunol. 2010; 184(9):5186-92. PMC: 2877909. DOI: 10.4049/jimmunol.0902938. View

Gottwein E, Corcoran D, Mukherjee N, Skalsky R, Hafner M, Nusbaum J . Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines. Cell Host Microbe. 2011; 10(5):515-26. PMC: 3222872. DOI: 10.1016/j.chom.2011.09.012. View

Yang Y, Chaerkady R, Kandasamy K, Huang T, Selvan L, Dwivedi S . Identifying targets of miR-143 using a SILAC-based proteomic approach. Mol Biosyst. 2010; 6(10):1873-82. PMC: 3812686. DOI: 10.1039/c004401f. View

Glaunsinger B, Ganem D . Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis. J Exp Med. 2004; 200(3):391-8. PMC: 2211977. DOI: 10.1084/jem.20031881. View

Carroll P, Kenerson H, Yeung R, Lagunoff M . Latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol. 2006; 80(21):10802-12. PMC: 1641760. DOI: 10.1128/JVI.00673-06. View

Jansen T, Hortmann M, Oelze M, Opitz B, Steven S, Schell R . Conversion of biliverdin to bilirubin by biliverdin reductase contributes to endothelial cell protection by heme oxygenase-1-evidence for direct and indirect antioxidant actions of bilirubin. J Mol Cell Cardiol. 2010; 49(2):186-95. DOI: 10.1016/j.yjmcc.2010.04.011. View

Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O . Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe. 2009; 5(4):376-85. DOI: 10.1016/j.chom.2009.03.003. View

10.

Dolken L, Malterer G, Erhard F, Kothe S, Friedel C, Suffert G . Systematic analysis of viral and cellular microRNA targets in cells latently infected with human gamma-herpesviruses by RISC immunoprecipitation assay. Cell Host Microbe. 2010; 7(4):324-334. DOI: 10.1016/j.chom.2010.03.008. View

11.

Yeligar S, Machida K, Kalra V . Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem. 2010; 285(46):35359-73. PMC: 2975160. DOI: 10.1074/jbc.M110.138636. View

12.

Djuranovic S, Nahvi A, Green R . miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science. 2012; 336(6078):237-40. PMC: 3971879. DOI: 10.1126/science.1215691. View

13.

McAllister S, Hansen S, Ruhl R, Raggo C, DeFilippis V, Greenspan D . Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood. 2004; 103(9):3465-73. DOI: 10.1182/blood-2003-08-2781. View

14.

Abend J, Ramalingam D, Kieffer-Kwon P, Uldrick T, Yarchoan R, Ziegelbauer J . Kaposi's sarcoma-associated herpesvirus microRNAs target IRAK1 and MYD88, two components of the toll-like receptor/interleukin-1R signaling cascade, to reduce inflammatory-cytokine expression. J Virol. 2012; 86(21):11663-74. PMC: 3486292. DOI: 10.1128/JVI.01147-12. View

15.

Lee H, Deng J, Xin H, Liu Y, Pardoll D, Yu H . A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors. Cancer Res. 2011; 71(11):3772-80. PMC: 3107358. DOI: 10.1158/0008-5472.CAN-10-3304. View

16.

Lei X, Zhu Y, Jones T, Bai Z, Huang Y, Gao S . A Kaposi's sarcoma-associated herpesvirus microRNA and its variants target the transforming growth factor β pathway to promote cell survival. J Virol. 2012; 86(21):11698-711. PMC: 3486299. DOI: 10.1128/JVI.06855-11. View

17.

Coscoy L, Ganem D . A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation. J Clin Invest. 2001; 107(12):1599-606. PMC: 200195. DOI: 10.1172/JCI12432. View

18.

Ziegelbauer J, Sullivan C, Ganem D . Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs. Nat Genet. 2008; 41(1):130-4. PMC: 2749995. DOI: 10.1038/ng.266. View

19.

Skalsky R, Samols M, Plaisance K, Boss I, Riva A, Lopez M . Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol. 2007; 81(23):12836-45. PMC: 2169101. DOI: 10.1128/JVI.01804-07. View

20.

Malaguarnera L, Pilastro M, Quan S, Ghattas M, Yang L, Mezentsev A . Significance of heme oxygenase in prolactin-mediated cell proliferation and angiogenesis in human endothelial cells. Int J Mol Med. 2002; 10(4):433-40. View